When A Patient Has Increased Thickening Of The Skin And Increased Discoloration

1. What essential question does one still need to ask to help make the diagnosis?
2. What is the tentative diagnosis?
3. Can you list at least three differential diagnoses?
4. What features in this condition differentiate it from other conditions?
5. What is the suitable treatment of this condition?

A 26-year-old African-American female presents with thickening of the skin on the soles and sides of her feet as well as discoloration on two of her toes. She says the discoloration and thickening started eight years ago and has slowly become worse over time.

The examination revealed no thickening on any other part of the body and there was no depigmentation elsewhere on the body. She has no nail or hair involvement. It is not known whether this condition was present when she was an infant or a child. She recalls that it became much worse after a session at the nail salon where the staff rubbed her foot vigorously with a pumice stone. It is more so the thickening rather than the loss of coloration that is difficult for the patient.

The patient notes that her mother has a similar condition but it is not as severe. No other members of the extended family have the condition. The patient notes that she initially was using home remedies that her mother had used and believes these remedies may have made matters worse.

In terms of treatment, the patient has used various products with salicylic acid and urea under the care of a previous doctor with little success. She also notes that mechanical debridement has led to increased thickening of the skin.

The diagnosis is transgressive genetic keratoderma, which is a form of palmoplantar keratoderma (PPK).1 It consists of hyperkeratosis spreading from the soles (and palms) to the dorsum of the foot across the transgradient line splitting the dorsal skin from the plantar skin. These are rare conditions and are caused by mutations in the keratinocytes.

In this particular patient, there is also noticeable depigmentation in the lower extremity. This condition is known as leukoderma. Most reports show a higher incidence of leukoderma in darker-skinned patients but this may be a result of the ease with which one observes leukoderma on pigmented skin.2 In this patient, it is more so the hyperkeratosis that defines the condition than the leukoderma. The more common causes of leukoderma include: vitiligo, dermatitis (eczema), severe trauma, burns and deep skin infections.

The color of skin and hair comes from the production, transport and distribution of melanin. It is synthesized by melanocytes and transferred to the keratinocytes. Genetic defects can account for many pigmentation defects and can affect the process at many sites along the production of melanin.3

The color of lesions or keratodermas depends on the degree of vasodilation, epidermal thickness, the type and density of inflammatory infiltrate, and the amount and location of the melanin.4 The density of melanocytes is similar among all racial and ethnic skin types but they produce more melanin in darkly pigmented people. It is interesting that the dyspigmentation or loss of pigmentation appears to be exaggerated and more noticeable in darkly pigmented individuals.5 In ethnic skin, there is an exaggerated reaction of skin to illness, inflammation and trauma.6
Most of the inherited skin disorders are rare and of minimal medical significance. However, there are others that are life threatening and debilitating. Treatment is available for some conditions but for others, there is no management beyond diagnosis. Identification of a genodermatosis may require referral for a genetics evaluation if this involves a woman of childbearing age.7

Pertinent Insights On Skin Morphology

The PPKs are due to inherited genetic defects, which affect the structural components of the keratinocyte.8 Most keratin disorders exhibit autosomal dominant inheritance.9 In order to resist the mechanical traumas, the plantar region is equipped with highly specialized proteins such as keratins. These form the cytoskeleton of epithelial cells, which are important for structural integrity. In keratoderma, excessive production of altered keratin occurs.10

Patients can inherit these in both an autosomal dominant and recessive fashion. Palmoplantar keratodermas are divided into three subgroups according to their phenotype. Simple keratodermas manifest as lesions only on the palmoplantar skin whereas complex keratodermas are associated with lesions of non-volar skin, hair, teeth, nails or sweat glands. Syndromic keratodermas are associated with abnormalities of other organs such as deafness, cancer, cardiomyopathy and adrenal insufficiency.11

We can divide simple keratodermas into three main groups, the diffuse, focal and punctate PPK. In diffuse PPK, the pattern of keratoderma is uniform across the palmoplantar skin. In focal PPK, the keratoderma develops at pressure points or sites of trauma. Punctate keratoderma has numerous small hyperkeratotic nodules.

Diffuse epidermolytic PPK is the most common pattern of PPK and is also known as Vorner’s disease. It is autosomal dominant and presents within the first months of life. Diffuse non-epidermolytic PPK is also autosomal dominant, is seen early in infancy and is known as Unna-Thost disease.11

With diffuse non-epidermolytic PPK, the lesions on the skin in NEPPK are often susceptible to secondary dermophyte infection and hyperhidrosis is common. Nail changes may occur in both disorders.

Both the hyperkeratosis and erythematous patches can be triggered by trauma to the skin, temperature changes, UV exposure and emotional stress.

Focal palmoplantar keratoderma and punctate palmoplantar keratoderma are less common. Keratosis punctata palmaris et plantaris is an autosomal dominant PPK that develops at 12 to 30 years of age. Physical trauma can induce the lesions and paring and debridement can worsen them.12 The lesions may coalesce into a diffuse pattern on the soles.

Clinically, PPK is characterized by symmetrical keratosis to the palms and soles. In this patient, only the soles were involved. When the keratosis is intense, it may reach the lateral edges of the feet and hands. Some patients may have a red-bluish band that begins at the outer edge of the palms and quickly reaches the center and inner sides of the fingers and toes. Therefore, the plantar skin slowly moves into the dorsal skin “zone” and changes the skin morphology.13 Once the skin morphology changes, it is difficult for it to revert back to the original “dorsal skin.”

Essential Keys To The Differential Diagnosis

One would make the diagnosis on clinical distribution, associated features and the presence of the condition in the family history. The majority of these diseases are present at birth or early in life. It is not unusual that patients may not have any skin changes until they are much older. If a patient has late onset hyperkeratosis, the differential must include the following conditions: hyperkeratotic eczema, palmoplantar psoriasis, acquired punctuate keratoses, arsenical keratoses and chronic tinea pedis.8

Hyperkeratotic eczema is focal and highly pruritic. Steroidal agents control the condition.

In regard to palmoplantar psoriasis, there is a silvery scale to the presentation. This often occurs in association with nail/joint involvement and lesions at other skin sites.
Acquired punctuate keratoses are sometimes associated with malignancy.

With chronic tinea pedis, there is extensive hyperkeratosis that resolves completely with antifungal therapy.

A Guide To Common Complications With Keratodermas

Pain. In regard to keratodermas, patients have more pain with punctuate keratoderma on weightbearing areas.

Difficulty in walking. The thickening of the plantar epidermis produces a stiffness that blunts sensation and makes movements more difficult.

Secondary infections (particularly tinea pedis and pitted keratolysis). The inflammatory response due to the infection may exacerbate the skin thickening. The use of systemic antifungal agents may help to decrease the thickness.

There may also be psychological implications of having a condition that others see as something different.

What You Should Know About Treatment

Unfortunately, the treatment of palmoplantar keratodermas, a lifelong condition, has always been less than adequate. When it comes to these genodermatoses, one can treat the conditions but not necessarily resolve them.

The first-line treatment has been debridement and the use of topical keratolytic agents (alpha-hydroxy acids such as lactic acid, glycolic acid and urea–based emollients). These agents do not totally resolve the condition but may help in selected individuals. Antifungal agents, both topical and oral, are reportedly useful for secondary infections of the hyperkerartotic condition.14

Physicians can utilize systemic retinoids to treat severe and diffuse forms of palmoplantar keratodermas in order to normalize the hyperkeratotic skin. Retinoids are natural and synthetic, and have biological activities that resemble those of vitamin A. They affect cell growth and differentiation, as well as cellular adhesiveness. They also are anti-inflammatory and can affect sebaceous glands.

There are three main types of oral retinoids. They include: isotretinoin (Accutane, Roche Pharmaceuticals), which is formally indicated for severe recalcitrant nodular acne; acitretin (Soriatane, Stiefel), which is indicated for severe psoriasis; and bexarotene (Targretin, Eisai), which is indicated for cutaneous manifestations of T-cell lymphoma.15 Physicians use these medications off-label to treat palmoplantar keratodermas so referral to other specialists may be warranted.
Systemic retinoids are not recommended for female patients with childbearing potential because of the long-term treatment approach and their slow elimination from the body. Complications such as periosteal hyperostosis may occur and teratogenesis is the most serious side effect.15

The more common side effects include dryness of skin and mucous membranes, reduced stratum corneum thickness and altered skin barrier function. Systemic retinoids will usually cause xerosis of the skin with pruritus and peeling, and sometimes skin fissuring.

In other patients, systemic retinoids may cause nail thinning and paronychia. Continued use of systemic retinoids may cause bone pain and idiopathic skeletal hyperostosis with calcification of tendons and ligaments.15

Dr. Morse is the President of the American Society of Podiatric Dermatology. He is a Fellow of the American College of Foot and Ankle Surgeons, and the American College of Foot and Ankle Orthopedics and Medicine. Dr. Morse is board certified in foot surgery.